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Randomized Phase II Study of Immunization With MAGE-3/Melan-A/gp 100/NA17 Peptide-Pulsed Autologous PBMC and rhIL-12 With or Without Low Dose IL-2 Inpatients With Metastatic Melanoma

Phase 2
18 Years
Not Enrolling
Metastatic Melanoma

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Trial Information

Randomized Phase II Study of Immunization With MAGE-3/Melan-A/gp 100/NA17 Peptide-Pulsed Autologous PBMC and rhIL-12 With or Without Low Dose IL-2 Inpatients With Metastatic Melanoma

Based on the above preclinical and Phase I results, a logical strategy for a second
generation melanoma vaccine has emerged. A randomized Phase II study in metastatic melanoma
patients will be undertaken. Patients first will be HLA-typed; HLA-A2-positive patients will
be eligible for screening. When feasible, each patient will undergo a tumor biopsy to screen
for expression of MAGE-3, Melan-A, gplOO, and NAI 7 using RT-PCR and immunohistochemistry,
to determine whether T cells are present in the lesion, to measure cytokine gene expression
by RT-PCR, and to perform gene array analysis. In addition, blood cells will be analyzed for
certain parameters of T cell function.

Patients will be randomized to cohorts A (no IL-2) or B (with low-dose IL-2). For treatment,
peripheral blood will be collected and fractionated by density centrifugation to isolate
PBMC as a source of APC. The PBMC will be divided into four pools, each of which will be
incubated with one of the following peptides: MAGE-3, Melan-A, gp 100, or Ni 7A. The
peptide-loaded cells will then be washed and recombined into a single suspension in PBS, and
lethally irradiated. Approximately 120 x 106 pulsed cells will be injected subcutaneously at
a site near a lymph node not thought to be involved with tumor. The subcutaneous route has
been selected for the reasons of safety, efficacy in the preclinical model, and the goal of
targeting the vaccine to a draining lymph node. rhIL-12 (4 .tg straight dose) will then be
given subcutaneously adjacent to the vaccine site days 1,3, and 5 of each cycle. This dose
and schedule was found to be effective in our phase I study. In one-half of the patients
(cohort B), IL-2 (I MU straight dose) will be administered subcutaneously daily, days 7-18.
Re-immunization along with rhIL-12 followed by IL-2 (if assigned) will be performed at 3
week intervals as in cycle I.

On day 1 of each cycle, peripheral blood will be collected to measure peptide-specific IFN-y
production. Before treatment and after every 3 cycles, PBMC will be collected to quantify
peptide specific CD8 T cells by flow cytometric analysis with peptide/HLA-A2 tetramers, and
evidence for a molecular response will be assessed by performing RT-PCR. for melanoma
antigens on peripheral blood samples. In addition, prior to treatment, after the first 3
cycles, and at the time of going off- study, a tumor biopsy will be performed to assess the
immune response in the tumor microenvironment, including gene array analysis. It is hoped
that these studies will uncover the reason for lack of clinical response in patients with
residual tumors. Clinical response will be assessed as a secondary outcome.

Inclusion Criteria:

- Histologically-confirmed melanoma with evidence of metastatic disease, either by
radiologic or physical examination. In transit metastases are allowed. Biopsy should
be performed to reconfirm the diagnosis in cases of doubt.

- Life expectancy of at least 12 weeks.

- Karnofsky performance status index >/=70.

- Written informed consent

- Adequate hematopoietic, renal, and hepatic function

- LDH <1.25 x ULN

- HLA typing: patient must express HLA-A2.

- Tumor biopsy: patient must agree to undergo biopsy of accessible tumor before and
after therapy, when feasible, to study tumor cell properties and characteristics of
immune cells.

Exclusion Criteria:

- Significant cardiovascular disease, or cardiac arrhythmia requiring medical

- Pregnant or nursing women.

- Biological therapy in the 4 weeks prior to the start of dosing.

- Prior therapy with a melanoma vaccine containing MAGE-3, Melan-A, gplOO, NA17

- Patients with intrinsic immunosuppression, including seropositivity for HIV antibody.
Patient should be tested if risk factors are identified.

- Serious concurrent infection, including active tuberculosis, hepatitis B, or
hepatitis C.

- Concurrent systemic corticosteroids (except physiologic replacement doses) or other
immunosuppressive drugs (eg. cyclosporin A).

- Psychiatric illness that may make compliance to the clinical protocol unmanageable or
may compromise the ability of the patient to give informed consent.

- Active or history of autoimmune disease including but not limited to: rheumatoid
arthritis (RF-positive with current or recent flare), inflammatory bowel disease,
systemic lupus erythematosis (clinical evidence with ANA 1:80 or greater), ankylosing
spondylitis, scleroderma, multiple sclerosis, autoimmune hemolytic anemia, and immune
thrombocytopenic purpura.

- Active gastrointestinal bleeding or uncontrolled peptic ulcer disease. Presence of
untreated brain metastases. All patients must undergo brain imaging as part of the
pre-study evaluation. Only patients with no brain metastases, or with brain lesions
successfully treated by stereotactic radiation or surgical removal without recurrence
at 28 day follow-up, will be eligible.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary hypothesis is immunization of patients with 4 melanoma antigen peptides will induce augmented specific IFN-.-producing CD8+ T cells against all 4 antigens simultaneously, and to determine the clinical response rate.

Outcome Time Frame:


Safety Issue:


Principal Investigator

Thomas Gajewski, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Chicago


United States: Food and Drug Administration

Study ID:




Start Date:

February 2002

Completion Date:

May 2007

Related Keywords:

  • Metastatic Melanoma
  • metastatic melanoma
  • Melanoma



The University of ChicagoChicago, Illinois  60637